Subscriber access provided by UNIV AUTONOMA DE COAHUILA UADEC
Letter
Diacetal Ditellurides as High Active and Selective Antiparasitic Agents towards Leishmania amazonensis Pamela Taisline Bandeira, João Pedro A. Souza, Débora B. Scariot, Francielle P. Garcia, Celso Vataru Nakamura, Alfredo Ricardo Marques de Oliveira, and Leandro Piovan ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00060 • Publication Date (Web): 09 Apr 2019 Downloaded from http://pubs.acs.org on April 9, 2019
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Medicinal Chemistry Letters
Diacetal Ditellurides as High Active and Selective Antiparasitic Agents towards Leishmania amazonensis Pamela T. Bandeira,† João Pedro A. Souza,† Débora B. Scariot,§ Francielle P. Garcia,§ Celso V. Nakamura,§ Alfredo R. M. de Oliveira,† and Leandro Piovan†* † Department of Chemistry, Universidade Federal do Paraná, Curitiba 4106902, Brazil. § Health Sciences Center, Universidade Estadual de Maringá, Maringá 4115200, Brazil. KEYWORDS Organotellurium chemistry, ditellurides, antiparasitic agents, neglected tropical disease, Leishmania amazonensis. ABSTRACT: Leishmaniasis is a neglected tropical disease and a public health concern in at least 98 countries, affecting mainly the poorest populations. Pharmaceuticals and chemotherapies available for leishmaniasis treatment have several limitations, which clearly justify the efforts to find new potential antileishmanial drugs. In this context, antiprotozoal activities towards different Leishmania species have been reported for hypervalent tellurium compounds, which motivated us to investigate, for the first time, the leishmanicidal properties of some non-hypervalent diaryl ditellurides. Thus, this work describes in vitro activity against Leishmania amazonensis and the cytotoxicities of diaryl ditellurides. Ditelluride LQ7 revealed a strong leishmanicidal activity on promastigotes and amastigotes, at sub-micromolar levels (IC50 = 0.9 ± 0.1 μmol L-1 and 0.5 ± 0.1 μmol L-1, respectively) and presented selectivity indexes greater than reference drug miltefosine. This preliminary study suggests that diaryl ditellurides may be promising scaffolds for the development of new agents for leishmaniasis treatment.
Leishmaniasis is a parasitic infection caused by more than 20 species of protozoans of the genus Leishmania, which is transmitted to mammals via the bite of infected female sandflies. According to the World Health Organization (WHO), leishmaniasis is endemic in at least 98 tropical and temperate countries, both developed and developing, and it is considered to be a neglected tropical disease. Furthermore, about 1.5 to 2 million new cases occur annually, resulting in approximately 70,000 deaths per year, thus representing a public health concern.1 Clinical manifestations of leishmaniasis are divided into visceral, cutaneous or mucocutaneous forms. Among these, cutaneous leishmaniasis remains the most widespread manifestation of the disease, of which one of the etiological agents in South America is Leishmania amazonensis. Leishmania parasite has been demonstrated a complex life cycle, which alternates in two distinct stages: promastigote, which is the extracellular form found in the female sandflies vectors, and amastigote, the intracellular forms that replicates in the mammalian hosts and are responsible for the clinical symptoms. This complex biology of Leishmania parasite makes the development of new antileishmanial agents highly challenging.2 Currently, leishmaniasis treatment drugs include the pentavalent antimonials, represented by pentostam and glucantime. Amphotericin B is recommended as a second-line therapy. Additionally, all these drugs must be administered by parenteral route and, usually, exhibit variable or poor efficacy, high toxicity and relatively long periods of administration, which hinder the continuity of treatment.3 Miltefosine, the first oral drug available for leishmaniasis treatment, is generally more effective, but some factors like renal toxicity, potential teratogenicity and high cost limit the access and popularization.4,5 Since drugresistant Leishmania parasites emergence has increased significantly and conventional chemotherapies have several limitations,6,7 the relevance of research on new potential antileishmanial drugs is easily justified.
In this context, antiprotozoal activities of well-known electrophilic organic and inorganic hypervalent tellurium compounds (telluranes) have been reported for different Leishmania species (Figure 1). RT01 was evaluated against L. amazonensis promastigotes and presented IC50 value of approximately 4 μmol L-1 (2 μg mL-1).8 In vitro and in vivo activities of RF07 were determined against L. chagasi amastigotes and showed inhibitory effect at sub-micromolar concentrations (IC50 = 0.5 μmol L-1).9 In vitro efficacy of inorganic tellurane AS101 against L. donovani promastigotes has been recently reported with IC50 value of 27 μmol L-1.10 Among the well-known classes of organotellurium compounds, the largest studied set are diaryl ditellurides (RTeTeR, R = aryl), since most of them are solid, almost odorless, stable to air or/and light and, consequently, easily handled, unlike their repulsive dialkyl derivatives (R = alkyl).11 Moreover, these species are versatile because they have dual behavior as nucleophiles or electrophiles, depending on the nature of the other species involved. Toxicity data on organotellurium compounds are still scarce in the current literature.12 (Di)tellurides had been reported as highly toxic agents to the central nervous system of rodents13 and as potential inhibitors of squalene monooxygenases,14 but also as presenting a broad range of biological applications,15 including antioxidant,16 antibacterial,17 antifungical,18 anti-cancer19 and anti-inflammatory20 properties. To the best of our knowledge, there has been no investigation about antileishmanial activities of diaryl ditellurides. Thus, we report in vitro leishmanicidal activity of some diaryl ditellurides (LQ1, LQ6, LQ7 and LQ8) against Leishmania amazonensis (promastigotes and amastigotes) and cytotoxicity on non-infected macrophages.
ACS Paragon Plus Environment
ACS Medicinal Chemistry Letters 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 2 of 5 This work
Cl O Cl Te Cl Cl
Cl
O
N O
Te
O
Cl
Cl Cl Te Cl O
NH4
O Te
O
O Te
O RF07 L. chagasi amastigotes IC50 = 0.5 mol L-1 SI = 10
RT01 L. amazonensis promastigotes IC50 ~ 4 mol L-1
LQ7 L. amazonensis amastigotes IC50 = 0.5 mol L-1 SI = 18
AS101 L. dovani promastigotes IC50 = 27 mol L-1
Figure 1. Organic and inorganic tellurium compounds with antileishmanial activities
In order to evaluate the effect of substitution pattern, ortho (LQ8), meta (LQ6) and para-substituted (LQ7) diaryl ditellurides were prepared according to literature (Scheme 1).21,22 Firstly, bromoacetophenones were transformed into their corresponding cyclic acetals (2,2-dimethyl-1,3-dioxolanes), which was performed with ethylene glycol and p-toluenessulfonic acid (pTSA) in 69%-98% isolated yields, respectively (Scheme 1).23 Incorporation of acetal moiety was considered by two main reasons: they are compatible with basic conditions during the second step (use of organomagnesium and organolithium compounds, followed by oxidation in water)24 and cyclic acetal-containing substances have been described to have promising biological activities, including antileishmanial properties.25
Subsequently, LQ1, LQ6, LQ7, LQ8 and miltefosine were assayed against L. amazonensis promastigotes (extracellular forms) and leishmanicidal activities were expressed as IC50 values, defined by the inhibitory concentration able to kill 50% of the parasites in relation to the negative control (Table 1). The cytotoxic concentration on macrophage cell line J774A1, represented by the CC50 index (cytotoxic concentration able to kill 50% of the cells in relation to the untreated control), was also measured to establish the selectivity of tested compounds. Furthermore, the selectivity index (SI) was determined for each tested compound as the ratio between the CC50 and the corresponding IC50 value in promastigotes (Table 1).
Meta (1,2-bis(3-(2-methyl-1,3-dioxolan-2-yl)phenyl)ditellane, LQ6) and para (1,2-bis(4-(2-methyl-1,3-dioxolan-2yl)phenyl)ditellane, LQ7) ditellurides were obtained as almost odorless red solids and were synthesized in 67% and 59% yields, respectively, by reaction between proper brominated precursor and magnesium, followed by elemental tellurium insertion and subsequently air oxidation (Scheme 1). This approach was not efficient to ortho-substituted derivative, therefore, LQ8 was synthetized by reaction of aryl lithium acetal (generated by brominelithium exchange) with elemental tellurium followed by air oxidation to give the product (1,2-bis(2-(2-methyl-1,3-dioxolan-2yl)phenyl)ditellane) as almost odorless yellow solid in 51% yield (Scheme 1). Diphenyl ditelluride (LQ1) was also prepared by reaction between phenylmagnesium bromide and elemental tellurium (Scheme 1), in order to evaluate the influence or necessity of substituents in benzene ring in further biological activity assays. All structures were characterized by 1H and 13C NMR and the insertion of tellurium was confirmed by 125Te NMR analyses. Spectroscopic data (1H, 13C and 125Te NMR) of compounds are in agreement with literature20 data and are available in Supporting Information.
Table 1. In vitro activity, cytotoxicity and selectivity index of LQ1, LQ6, LQ7, LQ8 and miltefosine
Br
O
Br
i. Mg0, THF, rt, 2h
Te
ii. Te0 , rt, 2h iii. O2
LQ1 (64%)
Ethyleneglycol pTSA, toluene reflux, 24h
O O
Br
Te
i. Mg0, THF, rt, 2h
O
Te
O
ii. Te0 , rt, 2h iii. O2 i. t-BuLi, THF, -78°C, 2h ii. Te0, 0°C - rt, 2h iii. O2
O Te
O
meta, LQ6 (67%) para, LQ7 (59%) O O Te
Te O O
ortho, LQ8 (51%)
Scheme 1. Synthesis of the diaryl ditellurides LQ1 and LQ6-8 from the corresponding brominated precursors.
Entry
Substance
Promastigote IC50 [a]
Macrophage CC50 [b]
(μmol L-1)
(μmol L-1)
Selectivity Index[c] (SI)
1
LQ1
1.4 ± 0.3
59 ± 9
2
LQ6
0.9 ± 0.2
22 ± 4
42 25
3
LQ7
0.9 ± 0.1
177 ± 5
194
4
LQ8
8.0 ± 1.4
19 ± 1
2
5
Miltefosine
20.7 ± 0.2
55 ± 2
3
Data are expressed as the mean ± SD determined in three different experiments. [a] IC50: the concentration required to give 50% inhibition. [b] CC50: Against macrophages after 72 h. [c] Selectivity Index: CC50/IC50.
Biological assays evidenced that all screened diaryl ditellurides exhibited greater activities against L. amazonensis promastigotes than reference miltefosine (Table 1). The most active substances were meta (LQ6) and para-substituted (LQ7) diaryl ditellurides, with submicromolar IC50 values of 0.9 ± 0.2 and 0.9 ± 0.1 μmol L-1 (corresponding to about 0.53 μg mL-1, entries 2 and 3 – Table 1), respectively, about 20-fold more active than miltefosine (IC50 = 20.7 ± 0.2 μmol L-1, corresponding to 8.15 μg mL-1, entry 5, Table 1). Diphenyl ditelluride (LQ1), the unsubstituted derivative, was slightly less active (IC50 = 1.4 ± 0.3 μmol L-1, entry 1 – Table 1) than disubstituted analogues LQ6 and LQ7. This result may indicate that the presence of substituents on the aromatic ring did not have a pivotal role in antileishmanial effect. However, when orthosubstituted analogue LQ8 was evaluated against L. amazonesis promastigotes, it presented IC50 = 8 ± 1 μmol L-1 (entry 4 - Table 1), which was about 8-fold less active than LQ1, LQ6 and LQ7, indicating that ortho-substitution pattern led to a decrease in antileishmanial activity. Despite the lower antileishmanial potential, it is worth noting that LQ8 presented activity about 3-fold higher than miltefosine.
ACS Paragon Plus Environment
Page 3 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Medicinal Chemistry Letters Since preliminary in vitro evaluation demonstrated that LQ6-8 have significant inhibitory effect on L. amazonensis promastigotes, they were evaluated through determination of cytotoxicity on host macrophages. The most selective substance was para-substituted ditelluride LQ7, which presented a CC50 of 177 ± 5 μmol L-1 and a selectivity index (SI) of 194 (entry 2, Table 1). In other words, LQ7 was about 194-fold more selective for L. amazonensis protozoa than healthy reference cells. Moreover, LQ7 was much less toxic to host macrophages than the reference, exceeding SI of miltefosine by 74fold (entry 5, Table 1).
dependent cysteine protease, including cathepsins.29 Furthermore, Barbiéri and coworkers described a possible relationship between the leishmanicidal effect of organotelluranes and cathepsin B inhibition, based on in vivo studies.9 Ditellurides present well-known dual nucleophilic or electrophilic behavior which allows us to propose ditellurides as electrophiles in inhibition of some thiol-dependent enzymes of L. amazonensis. This hypothesis could also explain the decrease in activity observed for LQ8, since Te atoms in this ditelluride are richer in electrons than LQ6 and LQ7. Another point to be considered is steric hindrance intrinsic to ortho position.
The second most selective substance was unsubstituted derivative LQ1, with CC50 = 59 ± 9 μmol L-1 and SI = 42 (entry 1, Table 1), which was also less toxic to host cells than miltefosine. LQ1 presented lower selectivity index than LQ7 (SI = 194, entry 5, Table 1) and this result suggests that para-substituted pattern has a pivotal role in the cytotoxic potential of screened diaryl ditellurides. This hypothesis could be confirmed when CC50 values of meta (LQ6) and ortho-substituted (LQ8) analogues were determined. Despite being highly selective, LQ6 and LQ8 presented higher cytotoxicity (CC50 = 22 ± 5 and 19 ± 1 μmol L-1, entries 2 and 4, Table 1, respectively) than para (LQ7) and unsubstituted (LQ1) analogues, which implied in lower selectivity indexes (SI = 25 and 2, Table 1). Notwithstanding the minor selectivity, LQ6 was about 10-fold more selective than miltefosine. LQ8 was the least selective substance, suggesting that the ortho substitution pattern has a negative influence on toxicity of diaryl ditellurides.
Subsequently, the effect of the most active substance LQ7 on the intracellular amastigotes was investigated (Table 2). In vitro evaluation demonstrated that LQ7 has significant inhibitory effect against amastigotes infection on Leishmania amazonensis at submicromolar concentration (IC50 = 0.5 ± 0.1 μmol L-1, Table 2, entry 1). Although the cytotoxicity of LQ7 was higher than that of the reference drug (CC50 = 8.3 ± 0.2 and 20.3 ± 0.5 μmol L-1, Table 2, entries 1 and 2, respectively), the SI value (18, entry 1, Table 2) demonstrated that this diaryl ditelluride has great potential as an antileishmanial agent.
The effects of substituents in ortho position in aromatic tellurium compounds have been studied extensively since 1970.26 It has been found that tellurium frequently interacts with a nearby heteroatom (O, N, S, P), producing quasi-cyclic systems. This phenomenon can be explained by assuming a non-covalent interaction between tellurium and a lone pair of electrons from the donor heteroatom, which interact with the antibonding orbital of tellurium atom (σ* Te-R).27 Since the oxygen atom in acetal group is capable of coordination with the tellurium in ortho position, an enrichment of electronic density in tellurium can be observed in LQ8. The existence of the non-covalent intramolecular interaction O → Te was clearly evidenced by 125Te NMR analysis (Figure 2), where ortho-substituted compound LQ8 presented lower chemical shift (Te = 369 ppm) than those of LQ7 (Te = 408 ppm) and LQ6 (Te = 426 ppm), para and meta-substituted, respectively. This non-covalent interaction causes an increase in electronic density in tellurium in LQ8, justifying the greater shielding and, therefore, the lowest chemical shift when compared to derivatives LQ6 and LQ7, which do not have this kind of intramolecular interaction.
Table 2. In vitro activity, cytotoxicity and selectivity index of LQ7 and miltefosine against intracellular amastigotes
Entry
Substance
Amastigote IC50
Macrophage CC50
Selectivity Index[a] (SI)
(μmol L )
(μmol L )
1
LQ7
0.5 ± 0.1
8.3 ± 0.2
18
2
Miltefosine
1.7 ± 0.1
20. 3 ± 0.5
12
-1
-1
Data are expressed as the mean ± SD determined in three different experiments. [a] CC50/IC50. Considering a possible hydrolysis of ketal group under the assays conditions, corresponding acetyl derivative LQ64 was prepared through the deprotection of LQ7 under acid conditions and reflux (Scheme 3, See Supporting Information) and, then its cytotoxicity evaluated (Table 3). The CC50 value of LQ64 (53 ± 2 μmol L-1) was lower than that observed to LQ7 (177 ± 5 μmol L-1μM) indicating that this compound is more toxic to healthy cells than LQ7. This result suggests that the compound LQ7 do not suffer alterations in evaluated media and is responsible for the activity and cytotoxicity observed in performed assays.
O Te
O
O Te
pTSA, acetone
Te
Te
reflux, 6h
O
O
LQ7
95%
O
LQ64
Scheme 3. Deprotection reaction of LQ7 to acetyl derivative LQ64
Table 3. In vitro cytotoxicity of LQ7, LQ64 and miltefosine against non-infected macrophages Entry Figure 2. 125Te NMR spectra of diaryl ditellurides LQ6, LQ7 and LQ8 (126.2 MHz, PhTeTePh ( = 422), 30 °C)
Leishmania parasites have been described as containing high levels of thiol-dependent enzymes, for example cathepsin B, a cysteine protease which has been found to be involved in all the life cycle stages of the parasites.28 Electrophilic hypervalent organotellurium compounds have also been described as potent inhibitors of thiol-
Substance
Macrophage CC50 (μmol L-1)
1
LQ7
177 ± 5
2
LQ64
53 ± 2
3
Miltefosine
55 ± 2
Data are expressed as the mean ± SD determined in three different experiments.
ACS Paragon Plus Environment
ACS Medicinal Chemistry Letters 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
In summary, ditellurides exhibited substantially higher SI values than the reference drug and, in the most remarkable case, SI of the compound LQ7 on the extracellular form of L. amazonensis exceeded that of the reference drug by 74-fold. Moreover, LQ7 also exhibited significant in vitro efficacy against intracellular amastigotes at submicromolar concentration (IC50 = 0.5 ± 0.1 μmol L-1). In attempt to better insight the activity, ditellurides with other substitution patterns need to be investigated, as well as the mechanism of action of these substances. These results suggest diaryl ditellurides as promising scaffolds for development of new agents leishmaniasis treatment.
ASSOCIATED CONTENT Supporting Information Synthetic procedures, biological assays protocols and NMR (1H, 13C and 125Te) data of compounds are available in Supporting Information (PDF).
AUTHOR INFORMATION Corresponding Author *Tel.: +55-041-3361-3178; e-mail:
[email protected] ACKNOWLEDGMENT The authors would like to thank National Council for Scientific and Technological Development (CNPq, Brazil, Proc. 456834/2014) and Coordination for the Improvement of Higher Level Personnel (CAPES) for financial support and fellowships.
REFERENCES 1 World Health Organization: Weekly Epidemiological Record (WER). 2016, 91, 285–296. http://www.who.int/wer/2016/wer9122/en/ (accessed May 20, 2018). 2 Séguin, O.; Descoteaux, A.; Leishmania, the phagosome, and host responses: The journey of a parasite. Cell Immunol. 2016, 309, 1-6. 3 Monge-Maillo, B.; López-Vélez, R. Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations. Clin. Infect. Dis. 2015, 60, 1398-1404. 4 Dorlo, T.P.; Balasegaram, M.; Beijnen, J.H.; de Vries, P.J. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J. Antimicrob. Chemother. 2012, 67, 2576-2597. 5 Sunyoto, T.; Potet, J.; Boelaert, M. Why miltefosine—a lifesaving drug for leishmaniasis—is unavailable to people who need it the most. BMJ Glob Health, 2018, 3, e000709. 6 Croft, S. L.; Sundar, S.; Fairlamb, A. H. Drug resistance in leishmaniasis. Clin Microbiol Rev. 2006, 19, 111-126. 7 Yasinzai, M.; Khan, M.; Nadhman, A.; Shahnaz, G. Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives. Future Med Chem. 2013, 5, 1877–1888. 8 Lima, C. B. C.; Arrais-Silva, W. W.; Cunha, R. L. O. R.; Giorgio, S. A novel organotellurium compound (RT-01) as a new antileishmanial agent. Korean J. Parasitol. 2009, 47, 213-218. 9 Pimentel, I. A. S.; Paladi, C. S.; Katz, S.; Judice, W. A. S.; Cunha, R. L. O. R.; Barbiéri, C. In vitro and in vivo activity of an organic tellurium compound on Leishmania (Leishmania) chagasi. PLoS One, 2012, 7, e48780-7. 10 Vishwakarma, P.; Parmar, N.; Chandrakar, P.; Sharma, T.; Kathuria, M.; Agnihotri, P. K.; Siddiqi, M. I.; Mitra, K.; Ka, S.; Ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate cures experimental visceral leishmaniasis by redox modulation of Leishmania donovani trypanothione reductase and inhibiting host integrin linked PI3K/Akt pathway. CMLS. 2018, 75, 563–588. 11 Comasseto, J. V. Selenium and tellurium chemistry: historical background. J. Braz. Chem. Soc. 2010, 21, 2027-2031. 12 Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem. Rev. 2004, 104, 6255 - 6284.
13 Pinton, S.; Luchese, C.; Stangherlin, E. C.; Roman, S. S.; Nogueira, C. W. Diphenyl ditelluride induces neurotoxicity and impairment of developmental behavioral in rat pups. J. Braz. Chem. Soc. 2010, 21, 2130-2137. 14 Laden, B. P.; Porter, T. D. J. Inhibition of human squalene monooxygenase by tellurium compounds: evidence of interaction with vicinal sulfhydryls. Lipid Res. 2001, 42, 235-240. 15 Cunha, R. L.O.R.; Gouvea, I. E.; Juliano, L. A glimpse on biological activities of tellurium compounds. An. Acad. Bras. Cienc. 2009, 81, 393-407. 16 Yu, F.; Li, P.; Wang, B.; Han, K. Reversible near-infrared fluorescent probe introducing tellurium to mimetic glutathione peroxidase for monitoring the redox cycles between peroxynitrite and glutathione in vivo. J. Am. Chem. Soc. 2013, 135, 7674 – 7680. 17 Shaaban, S.; Sasse, F.; Burkholz, T.; Jacob, C.; SAR studies on hydropentalene derivatives- Important core units of biologically active tetramic acid macrolactams and ptychanolides. Bioorg. Med. Chem. 2014, 22, 3610-3619. 18 Zakrzewski, J.; Huras, B.; Kiełczewska, A.; Krawczyk, M. Reactions of nitroxides 16. First nitroxides containing tellurium atom. RSC Adv. 2016, 6, 98829-35. 19 Engman, L.; Al-Maharik, N.; McNaughton, M.; Birmingham, A.; Powis, G. Thioredoxin reductase and cancer cell growth inhibition by organotellurium antioxidants. Anti-Cancer Drugs. 2003, 14, 153– 161. 20 Doering, M.; Diesel, B.; Gruhlke, M. C. H.; Viswanathan, U. M.; Manikova, D.; Chovanec, M.; Burkholz, T.; Slusarenko, A. J.; Kiemer, A. K.; Jacob, C. Selenium- and tellurium-containing redox modulators with distinct activity against macrophages: possible implications for the treatment of inflammatory diseases. Tetrahedron. 2012, 68, 10577-10585. 21 Haller, W. S.; Irgolic, K. J. Diaryl Ditellurides from grignard reagents and elemental tellurium. J. Organometal. Chem.1972, 38, 97 – 103. 22 Wirth, T.; Fragale, G. Asymmetric addition reactions with optimized selenium electrophiles. Chem. Eur. J. 1997, 3, 1894 – 1902. 23 Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 5ª ed., Prentice Hall: London, 1994. 24 Pietrasiak, E. Togni, A. Synthesis and characterization of fluorinated hypervalent tellurium derivatives. Organometallics 2017, 36, 3750−3757. 25 Aponte, J. C.; Castillo, D.; Estevez, Y.; Gonzalez, G.; Arevalo, J.; Hammond, G. B.; Sauvain, M. In vitro and in vivo anti-Leishmania activity of polysubstituted synthetic chalcones. Bioorg. Med. Chem. Lett. 2010, 20, 100-103. 26 Sudha, N.; Singh, H. B. Intramolecular coordination in tellurium chemistry. Coord. Chem. Rev. 1994, 135, 469-515. 27 Mukherjee, A. J.; Zade, S. S.; Singh, H. B.; Sunoj, R. B. Organoselenium chemistry: role of intramolecular interactions. Chem. Rev. 2010, 110, 4357–4416. 28 Somanna, A.; Mundodi, V.; Gedamu, L. Functional analysis of cathepsin B-like cysteine proteases from Leishmania donovani complex. Evidence for the activation of latent transforming growth factor beta. J Biol Chem. 2002, 277, 25305–25312. 29 Piovan, L.; Alves, M. F. M.; Juliano, L.; Bromme, D.; Cunha, R. L. O. R.; Andrade, L. H. Structure-activity relationships of hypervalent organochalcogenanes as inhibitors of cysteine cathepsins V and S. Bioorg. Med. Chem. 2011, 19, 2009-2014.
ACS Paragon Plus Environment
Page 4 of 5
Page 5 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Medicinal Chemistry Letters
Diacetal Ditellurides as High Active and Selective Antiparasitic Agents towards Leishmania amazonensis Pamela T. Bandeira,† João Pedro A. Souza,† Débora B. Scariot,§ Francielle P. Garcia,§ Celso V. Nakamura,§ Alfredo R. M. de Oliveira,† and Leandro Piovan†*
O O
Te
O Te
O
para >> meta > ortho
ACS Paragon Plus Environment
5
